Novel immune-escape uricase for treatment of hyperuricemia

治疗高尿酸血症的新型免疫逃逸尿酸酶

• 批准号: 10696609
• 负责人: Hiep T Tran
• 金额: $ 30万
• 依托单位: ABZYME THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-22 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696609
• 关键词: Adult; Affect; Affinity Chromatography; Animal Model; Antibodies; Bacteria; Binding; Biological Assay; Biological Products; Catalytic Antibodies; Cell Culture Techniques; Cell Separation; Cell surface; Cells; Chinese Hamster Ovary Cell; Clinical; Clinical Trials; Complication; Crystal Formation; DNA sequencing; Data; Deposition; Diploidy; Engineering; Enzyme-Linked Immunosorbent Assay; Enzymes; Escherichia coli; Evolution; Galactose; Generations; Genes; Genetic; Goat; Gout; Hyperuricemia; Immune; Immune system; Immunoglobulin G; Immunologic Surveillance; Individual; Inflammatory Arthritis; Infusion procedures; Kidney Diseases; Letters; Libraries; Mammalian Cell; Measures; Molecular Weight; Monitor; Mus; Mutagens; Mutate; Mutation; Nature; Oryctolagus cuniculus; Patients; Pharmaceutical Preparations; Phase; Physiological; Polyethylene Glycols; Polysaccharides; Population; Postmenopause; Production; Proteins; Recombinants; Refractory; Risk; Serum; Signal Transduction; Soil; Sorting; Stains; Surface; System; T-Lymphocyte; Technology; Therapeutic; Treatment Efficacy; Tumor Lysis Syndrome; United States; Universities; Urate; Urate Oxidase; Uric Acid; Utah; Variant; Woman; Yeasts; activation-induced cytidine deaminase; analog; arthropathies; base; effective therapy; enzyme activity; expression vector; genetic variant; glycosylation; human disease; immunogenicity; improved; in vivo; innovation; large scale production; medical schools; men; novel; polyclonal antibody; pressure; prevent; scale up; small molecule inhibitor

Abstract. High serum urate levels (hyperuricemia) and subsequent monosodium urate crystal deposition cause gout, the most common inflammatory arthritis in men and postmenopausal women. Gout affects an estimated 9.2 million adults in the United States. Hyperuricemia is also a major complication in patients with tumor lysis syndrome. However, the management of hyperuricemia in gout patients is problematic. Currently, gout patients are treated with small molecule inhibitor urate-lowering drugs. Gout can progress to destructive arthropathy, deposition of monosodium urate (MSU) crystals (tophi), and nephropathy if urate- lowering drugs fail. For those patients, infusion of foreign uricases such as a recombinant fungal uricase (Raburicase) or recombinant mammalian uricase modified with polyethylene glycol (Pegloticase/Krystexxa) is indicated to control hyperuricemia and dissolve the MSU crystals. Unfortunately, the immunogenicity of the administered foreign uricase and the ubiquitous presence of anti-PEG antibodies in the population limit the therapeutic efficacy of Pegloticase/Krystexxa and prevent repeated treatment. We propose to develop a novel immune-escape uricase that is covered with a glycan shield and contains immune escape mutations. We have identified uricase from soil bacteria Terriglobus saanensis with excellent enzyme activity at physiological pH, and that can be expressed and secreted as an active enzyme in yeast and mammalian cells. Using Abzyme's maturation, surface display and secretion platform, a selected uricase will be displayed on yeast cell surfaces, subjected to continuous gene evolution and immune selection pressure. At the end of phase I, it is anticipated that as many as 2 unique functionally-active immune escape uricase variants with a significant reduction in or no binding to anti-uricase polyclonal antibodies will be isolated, expressed, purified, and characterized. In Phase II, the most promising molecules will be evaluated in animal models of induced gout pursuant to the submission of an IND application for the initiation of clinical trials. The novel uricase will offer a number of therapeutic advantages, including the facilitation of large-scale production and reduced immunogenicity.

抽象。高血清尿酸盐水平（高尿酸血症）和随后的尿酸盐结晶沉积 痛风是男性和绝经后女性最常见的炎症性关节炎。痛风会影响 估计美国有920万成年人。高尿酸血症也是高尿酸血症患者的主要并发症。 肿瘤溶解综合征然而，痛风患者高尿酸血症的管理是有问题的。 目前，痛风患者用小分子抑制剂降尿酸药物治疗。痛风可以进展到 破坏性关节病、尿酸盐（MSU）晶体沉积（痛风石）和肾病（如果尿酸盐）- 降低药物失败。对于这些患者，输注外源尿酸酶，如重组真菌尿酸酶， （Raburicase）或用聚乙二醇修饰的重组哺乳动物尿酸酶（Pegloticase/Krystexxx a）。 用于控制高尿酸血症和溶解MSU晶体。不幸的是， 施用外源尿酸酶和人群中普遍存在的抗PEG抗体限制了 Pegloticase/Krystexxx的治疗效果，并防止重复治疗。我们打算写一部小说 一种免疫逃逸尿酸酶，被聚糖盾覆盖并含有免疫逃逸突变。我们有 从土壤细菌Terriglobus saanensis中鉴定出在生理pH下具有优异酶活性的尿酸酶， 并且可以在酵母和哺乳动物细胞中作为活性酶表达和分泌。使用Abzyme 成熟、表面展示和分泌平台，选择的尿酸酶将展示在酵母细胞表面上， 受到持续的基因进化和免疫选择压力。预计在第一阶段结束时， 多达2种独特的功能活性免疫逃逸尿酸酶变体， 将分离、表达、纯化和表征与抗尿酸酶多克隆抗体的结合。在 第二阶段，最有希望的分子将在诱导痛风的动物模型中进行评估， 提交IND申请以启动临床试验。新型尿酸酶将提供许多 治疗优势，包括促进大规模生产和降低免疫原性。